Monroe Karetzky

Pathways Activated during Human Asthma Exacerbation as Revealed by Gene Expression Patterns in Blood

Background Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations. Methodology/Principal Findings Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations. Conclusions/Significance This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.

Right ventricular dysfunction in obstructive sleep apnoea: reversal with nasal continuous positive airway pressure

The incidence and pathogenesis of right ventricular dysfunction in obstructive sleep apnoea (OSA) remains controversial. Using nuclear ventriculography, the prevalence of right ventricular dysfunction (RVD) was therefore determined in obese patients with OSA, as well as their clinical characteristics, arterial blood gas values, spirometry and sleep parameters. The reversibility of RVD was evaluated after long-term use of nasal continuous positive airway pressure (nCPAP). We studied 112 obese patients with OSA by nuclear ventriculography, 35 with RVD (Group 1), 77 without RVD (Group 2), and 14 patients without OSA as controls (Group 3). Repeat nuclear ventriculography was performed in seven patients who used nCPAP nightly for 6-24 months. The mean right ventricular ejection fractions (RVEF) were 31%, 47% and 44% in Groups 1, 2 and 3, respectively. Group 1 also had a lower left ventricular ejection fraction (LVEF) of 55 vs 63% in Group 2. The OSA groups did not differ in mean spirometric or arterial blood gas values. Group 1 had a lower mean nocturnal arterial oxygen saturation (Sa,O2) of 82 vs 87% in Group 2, and a longer apnoea duration of 22.3 vs 19.2 s. All but two patients in Group 1 had either awake alveolar hypoventilation or an apnoea + hypopnoea index > 40 disordered breathing events.h-1. Repeat nuclear ventriculography after nCPAP revealed an increase in RVEF from 30 to 39%. In conclusion, right ventricular dysfunction is common in obstructive sleep apnoea, but it is reversible with nasal continuous positive airway pressure treatment and appears to be related to nocturnal oxygen desaturation.

Pulmonary manifestations of inhaled street drugs

S ince 1611, when the Jamestown colonists first harvested tobacco, America has witnessed almost 4 centuries of inhalation drug abuse. The first general misuse of tobacco and drugs (opiates) occurred during the 16th century, when these substances were used as a substitute for legal currency.1 Drug scares have come and gone in cycles. Today, America is in the midst of its third war against illicit drugs, and it may not be the last. During the 19th century, certain mood-altering substances, such as opiates and cocaine, were often regarded as compounds helpful in everyday

A rare case of acute respiratory distress syndrome secondary to acute lithium intoxication.

Lithium carbonate is a widely administered antimanic drug used for the treatment of bipolar disorder, schizoaffective disorder, and depression. Despite the established clinical efficacy of lithium, its usage must be approached with caution due to its narrow therapeutic index. Lithium poisoning results in multisystem toxicity, and characteristic clinical manifestations are directly correlated to serum lithium concentration. We describe a rather rare but fatal side effect of lithium: acute respiratory distress syndrome (ARDS) in a 46-year-old female on lithium for the treatment of bipolar disease. She was referred for generalized weakness, found in hemodynamic compromise, and had laboratory data significant for a lithium level of 3.3 mmole/L, needing emergent hemodialysis. Subsequently, she developed hypoxic respiratory failure requiring intubation. Her chest x-rays showed new bilateral pulmonary edema, the computed tomography scan showed extensive alveolar consolidation and V/Q scan of low probability for pulmonary embolism. She underwent 3 dialysis sessions and supportive care and was able to be extubated in 5 days. To our knowledge, 4 cases of ARDS after the onset of lithium toxicity have been documented. All patients presented with altered mental status at serum lithium levels ranging from 3.8 to 4.9 mmole/L and cardiogenic etiologies in addition to other likely causes of ARDS were ruled out in each case. The patients were treated with saline hydration (50%) or hemodialysis (50%), indicating that hemodialysis may be a permissive factor in lithium-associated ARDS development rather than a required component. Taken together, we believe that lithium is a likely culprit in the initiation of ARDS and propose the addition of ARDS to the family of clinical manifestations of severe lithium toxicity.

Thallium-201 scintigraphy in the evaluation of graft dysfunction in lung transplantation. Newark Beth Israel Medical Center Lung Transplant Group

The object of this study was to evaluate graft dysfunction utilizing thallium-201 scintigraphy in patients who had undergone lung transplantation. We studied 11 patients who had undergone single-lung transplantation and had 44 evaluations for suspected graft dysfunction. All evaluations included a lung thallium-201 scan and chest radiography. In addition, 42 transbronchial biopsies, 19 gallium-67 scans and 28 pulmonary function tests were obtained. Rejection was defined by histopathology and/or the response to an empirical pulse of methylprednisolone, while cultures of protected specimen brushes and blood with a positive chest radiograph were used to define infection. The sensitivity of thallium scintigraphy for diagnosing rejection and/or infection (94%) was higher than that for transbronchial biopsy (86%), gallium scintigraphy (47%), chest radiography (67%), or spirometry testing (30%). Specificity was 100% for thallium scintigraphy and transbronchial biopsy, as compared to chest radiography and spirometry, which were 75 and 80% respectively. This study indicated that thallium-201 scintigraphy is useful for screening lung transplant recipients for episodes of acute rejection and/or infection. A positive scan is confirmation of graft parenchymal dysfunction and may then be followed by empirical treatment or bronchoscopy with transbronchial biopsy and culture to differentiate rejection and infection.

Evaluating control of breathing utilizing an on-line microcomputer

SummaryThis paper describes a system that was designed to evaluate ventilatory responses to hypercapnia, airway occlusion pressure (P100), as well as measuring ventilatory drive and timing. Parameters measured include minute ventilation

OVERDIAGNOSIS OF ASTHMA AND ITS RELATIONSHIP TO BODY MASS INDEX

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Utility of thallium‐201 scintigraphy in detecting right ventricular dysfunction in pulmonary embolism

, breathing rate (f), tidal volume (VT), inspiratory time (TI), fractional inspiratory time (TI/TTot), mean inspiratory flow (VT/TI), and end tidal partial pressure of carbon dioxide